1. Field of the Invention
This invention relates to a method for the prenatal detection of trisomy 21 in the second trimester by adjusting the risk of trisomy 21 based on fetal long bone biometry. More particularly, this invention relates to (a) measuring ultrasonically the biparietal diameter and the length of the femur, humerus, tibia, and fibula bones in fetuses of a patient population in the second trimester; (b) performing amniocentesis on the patient population in step (a) to determine which fetuses are normal and which fetuses have trisomy 21; (c) from the normal fetuses, deriving equations describing the predicted lengths of the femur, humerus, tibia, and fibula based on the biparietal diameter measurements; (d) calculating a ratio of observed lengths to predicted lengths of The femur, humerus, tibia, and fibula for all fetuses; (e) comparing the ratios calculated in step (d) for normal fetuses against the ratios calculated for fetuses having trisomy 21 and determining a threshold, as a percentile of these ratios, for abnormally short bone lengths in the fetuses having trisomy 21; and (f) employing the threshold determined in step (e) to detect prenatally trisomy 21 by fetal long bone biometry. In another embodiment, the method comprises the steps of (f) employing the threshold determined in step (e) to determine sensitivity and specificity in detecting prenatally trisomy 21 by fetal long bone biometry; and (g) employing the sensitivity and specificity determined in step (f) to adjust the risk of trisomy 21.
2. Description of the Background
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference. For convenience, the disclosures are referenced in the following text and respectively grouped in the appended bibliography.
Trisomy 21 (trisomy G, Down's syndrome, mongolism) is a condition characterized by a small, anteroposteriorly flattened skull, short, flat-bridged nose, epicanthal fold, short phalanges, and widened space between the first and second digits of hands and feet, with moderate to severe retardation, and associated with a chromosomal abnormality. In about 85% of cases of trisomy 21, there is an extra chromosome 21. Typically, the affected children are born to older mothers, but sporadic or trisomic mongolism may also occur in children of young mothers. The overall incidence of trisomy 21 is about 1:700 live births, but there is a marked variability depending on maternal age. In the early child-bearing years, the incidence of trisomy 21 is about 1:2000 live births whereas for mothers over 40, the incidence rises to about 45:1000 live births. Close to 50% of infants with trisomy 21 are born to mothers over 35. Nevertheless, recent studies have shown that the extra chromosome 21 can occasionally come from the father.
The use of ultrasonography in the prenatal detection of fetuses with trisomy 21 has been the subject of several reports .sup.1-17. The combination of various ultrasound markers for trisomy 21 has increased the sensitivity to 83%-91% with relatively low false positive rates ranging between 10% and 20% .sup.2,16. As a result, the use of ultrasound to adjust the risk for trisomy 21 has been advocated, and therefore the need for genetic amniocentesis in low as well as high risk patients .sup.16-17. In general, this approach requires special expertise which has prevented the incorporation of the "genetic" ultrasound into general practice. Although specific expertise is not required for measuring the femur, humerus, renal pelvis, or nuchal fold thickening, it is clear that expertise and experience are required to assess hypoplasia of the middle phalanx of the fifth digit, wide space between the first and second toe, and to diagnose structural malformations, especially cardiac defects. Therefore, simplification of sonographic detection of trisomy 21 would be desirable and would enhance the clinical applicability. Although there are several accounts reporting that fetuses with trisomy 21 are more likely to have short femur or humerus, there are no reports regarding the usefulness of tibia and/or fibula measurements in the prenatal detection of trisomy 21.